METAL-FREE SYNTHESIS of 2,3-DIHYDROQUINAZOLINONE DERIVATIVES USING 5-SULFOSALICYLIC ACID AS an ORGANOCATALYST Chandrakant D

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Original Research Article DOI: 10.26479/2020.0602.04 METAL-FREE SYNTHESIS OF 2,3-DIHYDROQUINAZOLINONE DERIVATIVES USING 5-SULFOSALICYLIC ACID AS AN ORGANOCATALYST Chandrakant D. Bhenki1, 2*, Shrikrishna S. Karhale1, Kiran N. Patil3, Vasant B. Helavi1 1. Department of Chemistry, Rajaram College, Kolhapur, (M.S.), India. 2. Department of Chemistry, Shri S. H. Kelkar College, Devgad, Sindhudurg, (M.S.), India. 3. Department of Chemistry, Dr.Ghali College, Gadhinglaj, Kolhapur, (M.S.), India

ABSTRACT: An efficient, selective and green protocol for the synthesis of 2,3- dihydroquinazolinone derivatives developed by the reaction of 2-aminobenzamide and aromatic aldehydes under metal-free conditions using 5-sulfosalicylic acid (5-SSA) as an organocatalyst in ethanol - water (1:1,v/v) system. The main advantages of this procedure include the use of an organocatalyst, practical simplicity, high yields, eco-friendly solvent, atom economy and ease of isolation of the product. Keywords: Organocatalyst, Metal-free synthesis, High atom economy,2,3-dihydroquinazolinones, Green protocol etc.

Article History: Received: March 10, 2020; Revised: March 29, 2020; Accepted: April 15, 2020.

Corresponding Author: Mr. Chandrakant D. Bhenki* Department of Chemistry, Shri S. H. Kelkar College, Devgad, Sindhudurg, Pin.: 416613, (M.S.), India, Email address: [email protected]

1.INTRODUCTION In several important natural and synthetic organic derivatives, the quinazolinone ring is observed.[1] It is a useful privileged scaffold for library design and drug discovery applications. [2] 2, 3-dihydroquinazolinone derivatives are reported as an anticancer, [3] antihypertensive agent.[4] 2, 3-dihydroquinazolinone derivatives having a broad range of potential biological and pharmacological activities,[5]as well as their importance in the preparation of drug molecules and natural product, therefore they becomes an important class of fused heterocycles.[6] Drugs having a quinazolinone ring are Diproqualone which is used as anti inflammatory and Methaqualone is © 2020 Life Science Informatics Publication All rights reserved Peer review under responsibility of Life Science Informatics Publications 2020 March – April RJLBPCS 6(2) Page No.52

Bhenki et al RJLBPCS 2020 www.rjlbpcs.com Life Science Informatics Publications used as antimalarial and currently being used for the assessment of the abuse liability of sedative - hypnotic drugs [7] as shown in Fig.1.

O O N OH N OH N N

Diproqualone Methaqualone Fig. 1. Biologically important scaffolds having quinazolinone skeleton. The increasing attention during the last decades for environmental protection has led both modern academic and industrial groups to develop less hazardous synthetic methodologies for organic synthesis. For the synthesis of biologically active organic molecules employing environmentally friendly organocatalyst has received much attention. Recently Hamzeh et al. found that the 5-SSA is used as a green catalyst for the synthesis of 1-amidoalkyl-2-naphthol by the reaction of 2- naphthol, substituted aldehyde and benzamide or acetamide. [8] Organocatalysts are simple organic molecules able to promote a wide range of chemical transformations.[9,10] They also typically have prominent characteristics including metal-free environment, relatively simple functionality, air stability, low cost, low toxicity and biological friendliness. [11,12] Search for more suitable preparation of 2,3-dihydroquinazolinone continues today. A particularly, catalyst suchasKAl(SO4)2.12H2O,[13]Fe3O4/Chitosen,[14]Al(H2PO4)3,[15]Zn(PFO)2,[16]SbCl3,[17](CeSO

4)2.4H2O,[18]SiCl4,[19]MWCNTS,[20]T3P,[21]Ionicliquid,[22]Tannicacid,[23]PEG400,[24]TBAB n ,[25]H-ZSM-5nanozeolite,[26]Fe3O4@SiO2-imid-PMA ,[27] etc. have been known to achieve this transformation. All these conventional methodologies have come across certain drawbacks such as transition metal catalyst, prolonged reaction times, tedious catalysts preparation and workup, use of toxic solvents. However the development of an efficient method , easy work up procedure, simple, environmentally benign protocol using a water soluble, metal-free catalyst and green solvent for the synthesis of quinazolinone derivatives is still desirable and in demand.[28] The development of organocatalyzed reactions in which the reactions are catalyzed by organic molecules is an important area for green synthesis. The use of water as the solvent increases the rate of the chemical reactions and also decreases the risk of organic solvent. Aqueous ethanol mixture for the reaction medium has worked wonderfully in many instances.[29] This offers a homogenous medium for many reactions and provides rate accelerations .[ 30] In continuation of our research in the development of environment-friendly methodologies for the synthesis of bioactive heterocyclic moieties. [31-34] In current work, we reported a novel methodology for the synthesis of 2,3-dihydroquinazolinone by ring closure of 2-aminobenzamide with substituted aromatic aldehydes, in the presence of 20 mol% 5-SSA in aqueous ethanol. To the best of our knowledge we develop this green methodology for the synthesis of an important class of fused heterocycles from cheap and easily available starting materials by employing cheap and easily © 2020 Life Science Informatics Publication All rights reserved Peer review under responsibility of Life Science Informatics Publications 2020 March – April RJLBPCS 6(2) Page No.53

Bhenki et al RJLBPCS 2020 www.rjlbpcs.com Life Science Informatics Publications available 5-SSA as an efficient organocatalyst in a green medium. 2. MATERIALS AND METHODS Experimental 5-sulfosalicylic acid (Spectrochem), 2-aminobenzamide (Thomas Baker), and aromatic aldehydes (Spectrochem and Thomas Baker) were used as received. All the reactions were carried out in dried glassware under an open atmosphere. The melting points of all purified synthesized compounds were recorded using a hot paraffin bath and are uncorrected. The IR spectra were recorded in the frequency range 500-4000 cm-1, on Alpha100508 FT-IR spectrometer. The NMR spectra were recorded on a Bruker Avance (400 MHz for 1H NMR and 100 MHz for 13C NMR) spectrometer using DMSO as solvent using Tetramethylsilane (TMS) as an internal standard. Chemical shifts (δ) are expressed in parts per million (ppm) values with the TMS as an internal reference, and coupling constants (J) are expressed in hertz (Hz). The Mass spectra of the purified product were recorded on a HRMS. General procedure for the synthesis of 2,3-dihydroquinazolin-4(1H)-one derivatives In 25 ml RB flask, a mixture of 2-aminobenzamide (1 mmol), aryl aldehyde (1 mmol), and 5- sulfosalicylic acid (20 mol%) in ethanol- water (1:1, v/v; 5 mL) was stirred at 80°C for a specified time (150 min – 240 min.) (Scheme 1 ) . Upon completion of the reaction as indicated by TLC, the reaction mixture was allowed to cool at room temperature and water (5 mL) was added and stirred continuously until solid was obtained in the reaction flask. The resultant solid was filtered, washed with water and then dried. The solid was recrystallized by pet ether: ethyl acetate (70:30, v/v). All the resulting products were pure and characterized by spectroscopic techniques.

O O CHO

NH NH 2 5-SSA (20mol%) + o N NH2 Ethanol:Water, 80 C R H R Scheme 1: Synthesis of 2,3-dihydroquinazolinone derivatives Spectral data of representative compounds 2-(4-nitrophenyl)-2,3-dihydroquinazolin-4(1H)-one (3b) (Table 3, entry 2) 1 Yellow Solis, Mp:198-199 °C, Yield = 92%, H NMR (400 MHz, CDCl3):δ = 6.74 - 6.76 (d, J = 8.4 Hz, 1 H), 8.22-8.25 (m, 1 H), 7.23-7.30(m, 2 H), 6.65-6.69 (m, 1 H), 5.89 (s, 1 H), 7.71- 13 7.74(d, J = 8.8 Hz, 1 H), 8.48 ( s, 1 H), 7.61 ( s, 1 H), CNMR (100 MHz, CDCl3): δ = 163.2, 149.2, 147.2, 147.1, 133.4, 127.3, 123.5, 177.4, 165.25. IR (KBr) cm–1: 3367, 3289, 3027, 1646, 1600, MS (ESI): m/z 270 [M +]. 2-(4-bromophenyl)-2,3-dihydroquinazolin-4(1H)-one (3c)( Table 3,entry 3) 1 Yellow Solid,Mp.196-197 °C, Yield =90%, H-NMR (400 MHz, CDCl3): δ = 7.56-7.25 (m, 5 H), 6.72-6.74 (d, J =8.0 Hz, 2 H), , 6.64-6.68 (m, 1 H), 5.74 (s, 1 H), 8.29 ( s, 1 H), 7.11, ( s, 1 H), 13C- © 2020 Life Science Informatics Publication All rights reserved Peer review under responsibility of Life Science Informatics Publications 2020 March – April RJLBPCS 6(2) Page No.54

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NMR (100 MHz, CDCl3):δ=163.4, 147.5, 141.0, 133.3, 131.1, 129, 127.3, 121.4, 117.2, 114.4, 65.75, IR (KBr): 3367, 3282, 3038, 1647, 1603,MS (ESI): m/z 303 [M +]. 3. RESULTS AND DISCUSSION Initially, we chose a reaction of 2-aminobenzamide with 4-nitrobenzaldehyde as a model reaction in order to investigate the effects of solvent, temperature and amount of catalyst on the yield of the product.(Scheme 2) O CHO O

NH 2 5-SSA, Ethanol:H2O NH

NH + o 2 80 C N H NO2 NO2 Scheme 2: Synthesis of 2-(4-Nitrophenyl)-2,3-dihydroquinazolin-4(1H)-one (3b). For this purpose, we have screened several solvents such as toluene, THF, methanol, water, ethanol, acetonitrile, methylene dichloride, ethanol- water (1:1) etc. It was observed that the non- polar solvents such as toluene gave only moderate yields of the products (55%) and the polar solvents (ethanol, acetonitrile, methylene dichloride and methanol) give a much better yield than toluene, THF also gave a good yield for the reaction. In pursuance of making this protocol greener and economical, it was found that ethanol-water (1:1) acts more superior than other solvents, and gave excellent yield (92%) for this reaction (Table 1, Entry 3). Table 1: Optimization of the reaction conditions using different solvents. a Entry Solvent Time(min) Yield (%)b

1 Toluene 180 55

2 THF 150 72

3 Ethanol : Water (1:1) 150 92

4 CH3CN 55 65

5 EtOH 60 78

6 MeOH 90 68

7 H2O 60 70 aReaction conditions : 2-aminobenzamide (1 mmol), 4-nitrobenzaldehyde (1 mmol), and 20 mol% 5-SSA in solvent (5 mL) at 800C temperature,bIsolated yields . We next investigated the reaction scope by varying the temperatures like RT, 45°C, 60°C,70°C, and 80°C using 30 mol% 5-SSA catalyst, to reduce the reaction time and increase the product yield. It was observed that most of the reactions of 2-aminobenzamide with aldehydes proceeded smoothly. However, the yields were slightly lower at room temperature (Table 2, entries 1), © 2020 Life Science Informatics Publication All rights reserved Peer review under responsibility of Life Science Informatics Publications 2020 March – April RJLBPCS 6(2) Page No.55

Bhenki et al RJLBPCS 2020 www.rjlbpcs.com Life Science Informatics Publications which may be due to the poor solubility of aldehydes in solvent, but the yields of the products were enhanced, when the reaction temperature was increased around 45°C - 80°C (Table 2, entries 2 - 9). Table 2: Optimization of temperature and catalyst concentrationa. Entry Temperature (°C) Catalyst Conc. (mol %) Yield (%)b 1 RT 30 45 2 45°C 30 60 3 60°C 30 65 4 700C 30 70 5 800C 5 78 6 800C 10 82 7 800C 15 85 8 800C 20 92 9 800C 30 92 a Reaction conditions: 2-aminobenzamide (1 mmol), 4-nitrobenzaldehyde (1 mmol), in ethanol:water (1:1,v/v) (5 mL) for 2.5 h ,bIsolated yields. Further to determine the optimum amount of 5-SSA , the same model reaction was carried out using varied concentrations of 5-SSA such as 5, 10, 15, and 20 mol%. In this study,the formation of the product was observed in 78%, 82%, 85% and 92% yield respectively. This indicates that 20 mol% of 5-SSA is sufficient to carry out the reaction smoothly. The yields are not enhanced obviously by further increasing the amount of catalyst. There is no effect on the reaction rate as well as the yield of the product, when the concentration of catalyst increased from 20 to 30 mol%. The reaction proceeds smoothly to give higher yield (92%), proves an increase in the amount of catalyst can enhance the yield. Therefore, 20 mol% has been selected as an optimum catalyst concentration. To make this protocol environmentally green and economically viable, 20 mol% 5- SSA was employed as a catalyst in ethanol-water (1:1, v/v) as the solvent, which furnishes the desired product in excellent yield (92%) at 80°C (Table 2, entry 8). The reasons behind the excellent catalytic reactivity of 5-SSA may be due to the presence of sulphonic acid functionality which plays the role of Bronsted acid catalyst thereby increases the electrophilicity of carbonyl carbon of aryl aldehydes. Further, its excellent solubility in aqueous ethanol forms a homogeneous solution with substrates and enhances the rate of reaction giving excellent yield in shorter reaction times. With optimized conditions in hand, we turned our attention towards the scope and generality of the protocol. For this purpose the reaction between 2-aminobenzamide and a variety of substituted aromatic benzaldehyde was carried out. Generally, the reactions were performed using 20 mol% of 5-SSA in water- ethanol (1:1, v/v) at 80°C temperature to give the desired

Bhenki et al RJLBPCS 2020 www.rjlbpcs.com Life Science Informatics Publications products in good to excellent yields. All the results are compiled in Table 3. It is observed that, aryl aldehyde with electron-donating as well as electron-withdrawing substituents reacted efficiently with equal chemical reactivity. The formation of the desired product was confirmed with the help of FT-IR, 1H NMR, 13C NMR and mass spectra. Table 3: 5-SSA catalyzed synthesis of 3a-3l a,b

O O CHO

NH NH 2 5-SSA (20mol%) + o N NH2 Ethanol:Water, 80 C R H R 1 2 (a - l ) 3(a - l ) Time Yieldb Mp (°C) Entries Aryl aldehyde Product Ref. (min) % (Reported) 1 Benzaldehyde 3a 150 88 216-218 (217-219) [35] 2 4-Nitrobenzaldehyde 3b 150 92 198-199 (200-201) [36] 3 4-Bromobenzaldehyde 3c 150 90 196-197 (197-198) [35] 4 3-Nitrobenzaldehyde 3d 150 84 196-198 (195-196) [35] 5 4-Hydroxybenzaldehyde 3e 240 86 279-280 (278-280) [35] 6 4-Methoxybenzaldehyde 3f 240 85 181-183 (182-184) [35] 7 4-Cyanobenzaldehyde 3g 150 88 251-252 (249-251) [35] 8 4-Methylbenzaldehyde 3h 180 84 225-227 (224-226) [35] 9 2,4-dimethoxybenzaldehyde 3i 180 92 184-185 (186-187) [35] 10 4-Chlorobenzaldehyde 3j 150 88 205-206 (204-206) [35] 11 2,5-dimethylbenzaldehyde 3k 150 84 220-221 (222-224) [37] 12 3,4-dihydroxybenzaldehyde 3l 180 86 285-286 (288-290) [37] a Reaction conditions : 2-aminobenzamide (1 mmol), aryl aldehyde (1 mmol), and 5-SSA (20 mol%) in ethanol:water (1:1) (5 mL) at 80 °C,b Isolated yield.

4. CONCLUSION In summary, we developed a green methodology for the synthesis of a variety of 2,3-dihydro-2- phenylquinazalin-4(1H)-one derivatives in excellent yield. One-pot reaction, metal-free synthesis, operational simplicity, atom economy, no waste generation, use of safe, cheap and environmentally benign solvent are key aspects of the present protocol. Further, the use of water soluble, recyclable, inexpensive, commercially available non-toxic catalyst as a potential and metal-free organocatalyst, fully green protocol and clean reaction profile, shorter reaction time and a wide range of substrate applicability, mild reaction condition, a high conversion rate etc.,are the important features of this method.

Bhenki et al RJLBPCS 2020 www.rjlbpcs.com Life Science Informatics Publications ETHICS APPROVAL AND CONSENT TO PARTICIPATE Not applicable. HUMAN AND ANIMAL RIGHTS No Animals/Humans were used for studies that are base of this research. CONSENT FOR PUBLICATION Not applicable. AVAILABILITY OF DATA AND MATERIALS The authors confirm that the data supporting the findings of this research are available within the article. FUNDING None. ACKNOWLEDGEMENT CDB is thankful to Management of Shikshan Vikas Mandal’s, Devgad, and Principal, Shri S. H. Kelkar Art`s, Commerce and Science College, Devgad, Dist. Sindhudurg, and Head, Department of Chemistry, Rajaram College, Kolhapur for encouragement and providing necessary facilities.We are greatfull to the Department of Chemistry, Shivaji University, Kolhapur, Maharashtra, India, the Department of Chemistry, Solapur University, Solapur, Maharashtra, India, for providing spectral data . CONFLICT OF INTEREST Authors have no any conflict of interest. REFERENCES 1. Maskey R P, Shaaban M, Wollny I G, Laatsch H J. Quinazolin-4-one Derivatives from Streptomyces Isolates . Nat Prod.2004; 67:1131-1134. 2. Welsch M E, Snyder S A, Stockwell B R. Privileged scaffolds for library design and drug discovery. Curr Opin Chem Biol.2010;14:347-361. 3. Xia Y, Yang Z.-Y, Hour M.-J., Kuo S-C, Xia P, Bastow K.F, et al Antitumor agents. Part 204: synthesis and biological evaluation of substituted 2-aryl quinazolinones. Bioorganic & medicinal chemistry letters, 2001; 11:1193-1196. 4. Honkanen E, Pippuri A, Kairisalo P, Nore P, Karppanen H, Paakkari I. Synthesis and antihypertensive activity of some new quinazoline derivatives. Journal of medicinal chemistry. 1983; 26:1433-1438. 5. Kim J S, Rhee H K, Park H J, Lee S K, Lee C O, Choo H P. Synthesis of 1-/2-substituted- [1,2,3]- triazolo [4,5-g]phthalazine-4,9-diones and evaluation of their cytotoxicity and topoisomerase II inhibition. Bioorg Med Chem. 2008; 16:4545-4550. 6. Wu J, Du X, Ma J, Zhang Y, Shi Q, Luo L, Song B, Yang S, Hu D. Preparation of 2,3-

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